Review: Myeloid Disorders Flashcards
What is the pathogenesis of problems caused by Acute Leukemias?
In Acute Leukemias/lymphomas, a proliferation of -blasts causes what?
Suppression of NL hematopoeisis
- Anemia
- 2. Thrombocytopenia
- 3. Neutropenia
What are differences seen in ALL and AML?
- ALL
- Lymphoblasts (TdT+)
- Children
- T-ALL = teenager and thymic mass
- AML
- Myeloblasts (MPO+ and auer rods)
- Older people >60
Myeloblasts are positive for what marker?
MPO (=> auer rods)
Markers for AML
- CD33+
- CD34+
Acute Myeloid Leukemia (AML)
Malignant proliferation of myeloblasts in the BM.
- Released into bloodstream = leukocytosis
- Fill up BM => supress of NL hematopoeisis (pancytopenia)
- Anemia,
- Thrombocytopenia
- Neutropenia
- M5 = gum infiltation (gingival hyperplasia)
In order to qualify as AML, on biopsy of the BM what must we see?
at least 20% of BM is myeloblasts
AML is MC in who?
- >60 YO Males
- If in younger adults: balanced translocations
- t(8:21)
- inv(16)
- t(15:17)
Most genetic abnormalities in AML..
- Most genetic abnormalities in AML interfere with TF that are required for NL myeloid cell to differentiate.
- Karyotypic aberrations are found in 90% of cases
Most common chromosomal rearrangements in AML
- t(8:21): disrupt RUNX1 gene (M2) ***
- inv(16): disrupt CBFB gene (M4) **
- t(15;17): PML- RAR-a fusion gene (Acute Promyelocytic Leukemia/M3); + FLT3 activating mutation
- t(11q23;v): involve MLL (M4/5)
RF for AML
- Alkylating chemotherapy
- Radiation
- MPD
- Down Syndrome (Also RF in ALL)
Clinical Presentation of Acute Myeloid Leukemia
Present with similar clinical picture as ALL: sx of pancytopemia
- Anemia = >Fatigue (anemia)
- Neutropenia => fever/ Opportunistic infections (fungi, pseudomonas, commensals and pneumocystis) of oral cavity, skin GI/GU tract.
- Thrombocytopenia => spontaneous mucosal and cutaneous bleeding (worse in APML)
- Petechiae, ecchymoses, mucosal hemorrhages and hematuria
M5 = AML with monocytic differentiation = gingival swelling and skin infiltration (leukemia cytis)
What are differences in clinical presentation of ALL and AML?
AML is LESS likely to present with (but still CAN)
- Bone pain
- LAD
- Hepatosplenomegaly
- CNS/testes spread
- Rarely presents as a mass
Diagnosis of Acute Myeloid Leukemia
- Myeloid specific antigen stains (MPO and non-specific esterases)
- BM exam is REQUIRED = >20% of myeloblasts in BM
WHO Classification of AML: Class 1, 2 and 3
What is Class I AML?
Prognosis?
AML + genetic aberrations
Favorable prognosis:
- t(8:21),
- inv(16)
Intermediate prognosis:
- t(15;17)
Poor prognosis:
- t(11;q23:v)
WHO Classification of AML: Class 1, 2 and 3
What is Class 2 AML?
Prognosis?
AML with MDS-like features
All have poor prognosis
- AML due to prior MDS
- MDS-like cytogenic aberrations
WHO Classification of AML: Class 1, 2 and 3
What is Class 3 AML?
Prognosis?
AML that is therapy related
All VERY POOR prognosis
- AML due to alkylating chemo/radiation
- Post- topoisomerase-II inhibitrs
What are the FAB Classification of AML?
- M0 =
- M1 =
- M2=
- M3 =
- M4 =
- M5a/b =
- M6a/b =
- M7 =
- M0 = Minimally differentiated AML
- M1 = AML without maturation
- M2= AML with myelocytic maturation
- M3 = Acute Promyelocytic Leukemia
- M4 = Acute myelomonocytic Leukemia (with myelomonocytic maturation)= AMML
- M5a/b = Acute Monocytic Leukemia (with monocytic maturation)
- M6a/b = Acute Erythroleukemia (with erythroid maturation)
- M7 = Acute Megakaryotic Leukemia (with megakaryocytic maturation)
Name this classifcation of AML:
Blasts lack cytologic and cytochemical markers of myeloblasts
M0 - AML, minimally differentiated
What do you see in
M1: AML without maturation
20% of cases
Very immature cells
- >3% are MPO(+)
- Few granules or Auer rods
What do you see in
M2: AML with myelocytic maturation
- t(8:21) = MC type (30-40%)
- All granulocytes have undergone myeloid maturation
- Auer rods are present
What do you see in
M3: Acute Promyelocytic Leukemia
- Pts are younger (35-40 yo)
- Most cells are hypergranular promyelocytes
-
t(15:17) with FLT3 activating mutation => PML-RARA fusion gene
- Chr 15 = Retinoic acid receptor- alpha (RARA) is dysfunctional: prevents NL maturation of promyelocytes => INC amounts of promyelocytes, which contains MANY Auer rods => if they leak out of cell => INC risk of DIC
What is the treatment for Acute Promyelocytic Leukemia?
All trans-retinoid acid (form of Vitamin A): ABNL cells will mature
What do you see in
M4: with myelomonocytic maturation (Acute myelomonocytic Leukemia/ AMML)
- Inv(16)
- Cells = Myelocytic and monocytic differention
- Myeloid cells = MPO +
- Monoblasts = Non-specific esterase (+), no auer rods and MPO (-)
What do you see in
M5 a/b = Acute monocytic Leukemia
O O O
- ONLY monoblasts (MPO-, non-specific esterase +)
- Older patients
- Organomegaly, LAD and tissue infiltration
- Swollen gums
- Fungal skin infections
- Leukemia cutis
- Orbital Granuloctic sarcoma
If AML occurs in younger patients, what translocations do we see?
- t(8:21) = disrupt RUNX1 gene
- inv (16) => disrupt CBFB gene
- t(15:17)
What is prognosis of AML?
Depends on pathogenesis:
- Overall, 60% achieve complete remission with chemotherapy; relapse is common.
t(5:17) = cured with all trans retinoic acid and arsenic salts
What are Myeloproliferative Disorders?
Mutation of a multipotent progenitor cells (Common myeloid progenitor) in the BONE MARROW results in a constitutively activated TK =>
- Pancytosis (high WBC, RBC and platelets)
- hypercellular marrow, BUT; 1 cell line is affected the MOST.
- Does NOT impair differentiation
Myeloproliferative disorders are MC in who?
Older adults
Myeloproliferative Disorders (4)
- Chronic Myeloid Leukemia: lots of granulocytes
- Polycythemia Vera: lots of RBC
- Essential thrombocytosis: lots of platelets
- Primary Myelofibrosis:
What are common clinical features of Myeloproliferative Disorders?
Suppression of NL hematopoiesis: Neoplastic cells and products displace NL BM
: tend to have thrombocytosis (?)
Extramedullary hematopoiesis: HSCs home at non-marrow sites
Bleeding: paradoxically occurs because the platelets are functionally ABNL
Transform into spent phase (marrow fibrosis + cytopenia) OR AML (or ALL, which has an even worse prognosis than becoming AML)
In Myeloproliferative Disorders, what cells are increased?
Cells of ALL myeloid lineages (WBC, RBC and platelets)
Common complications in Myeloproliferative Disorders
- Increased cell turnover => increase risk for hyperuricemia and gout
- Extramedullary hematopoeisis
- Bleeding
- Can progress to marrow fibrosis (spent phase)
- Can transform to acute leukemia (AML is MC, but ALL can occur to and if so, worse prognosis
What is Chronic Myelogenous Leukemia (CML)?
Mutation in HSC that causes proliferation of mature myeloid granulocytes (neutrophils and ESPECIALLY basophils)
*Basophilia is HIGHLY associated with ____
CML
Chronic Myelogenous Leukemia is due to what genetic abnormality?
t(9:22) Philadelphia Chr => BCR-ABL fusion gene => constitutive activation of ABL TK
1st line treatment for CML
Imatinib (blocks TK activity)
Clinical presentation of Chronic Myelogenous Leukemia
- Insidious onset of fatigue (anemia), WL, anorexia, +
- LUQ “dragging” abdominal pain due to splenomegaly (extramedullary hematopoiesis, expanded red pulp) that often contains infarcts of varying age
- Potential hepatosplenomegaly and lymphadenopathy
How do we diagnose Chronic Myeloid Leukemia?
- Leukocytosis (>100,000mm3, with immature forms < 10% blasts)
-
Hypercellular BM: ↑ maturing granulocyte precursors => ↑ eosinophils, basophils and megakaryocytes
- Sea-blue histiocytes
- INC reticulin
- t(9:22) BCR-ABL fusion gene
- Low LAP: helps to differentiate infection vs cancer.
How do we differentiate Chronic Myeloid Leukemia from Leukmoid Reaction?
- CML granulocytes are LAP (-)
- Increased basophils
- T(9:22)
What is a complication of CML?
Transformation into AML or ALL (can transform to either bc mutation is in HSC).
What is Polycythemia Vera?
Neoplastic proliferation of mature myeloid cells in BM, especially RBC.
What findings on CBC will a patient with Polycythemia Vera have?
- Leukocytosis (12,000-50,000)
- Thrombocytosis (>500,000)
- Erythrocytosis (higher relative to others, causing symptoms): ↑RBC mass. ↑ Hb, ↑ Hct = >60%
What is the genetic abnormality we see in Polycythemia Vera?
JAK2 point mutation: constitutive activation of JAK2 kinase (Valine = Phenylalanine at residue 617)
- (+) of JAK2 kinase
- Stimulates erythropoietin and thrombopoietin RECEPTORS
- ↑ production of RBC (RBC mass); ↑Hgb, Hct and RBC count
- Thus, due to negative FB, ↓ EPO.
In PV, what are O2 and EPO levels?
- O2 = NL
- EPO = low
To differentiate PV from other causes ↑ RBC mass/ Reactive polycythemia:
Reactive polycythemia due to lung disease (hypoxia)
Reactive polycythemia due to lung disease:
- PaO2 = ↓
- EPO = high
PV:
- paO2= NL
- EPO is ↓.
To differentiate PV from other causes ↑ RBC mass/ Reactive polycythemia:
Reactive polycythemia due to ectopic EPO production (RenalCC):
Reactive polycythemia due to ectopic EPO production (RenalCC):
- SaO2 = NL;
- EPO = high
PV:
- paO2= NL
- EPO is ↓
Clinical Presentation of Polycythemic Vera
What are the symptoms due to =>
Insidious onset, usually adults of late-middle age.
Symptoms due to ↑ RBC mass (Erythrocytosis)
-
Thrombosis (DVT, MI, stroke): often 1st symptom
- Budd-Chiari syndrome (thrombosis in hepatic vein => liver infarcts)
-
Erythrocytosis:
- Plethoric (too much blood in body)
- Cyanotic: HA/dizziness and HTN
- Hyperviscosity symptoms: blurry vision, HA.
- Basophilia = hot showers trigger histamine release => itching after warm bath or shower and peptic ulcers
- High cell turnover => hyperuricemia and symptoms of gout.
- Late in disease: organomegaly
High cell turnover è hyperuricemia and symptoms of gout.
Late in disease: organomegaly
Prognosis and treatment of PV
- Without treatment = death from bleeding or thrombosis within months.
- Plebotomy extends median survival to about 10 years
Complications of PV
- Budd-Chiari
- Hyperuricemia and gout
- Organomegaly
- Extensive marrow fibrosis can displace HSC => extramedullary hematopoeisis
JAK2 point mutation, which causes it to be active all the time, is occurs in what Myeloproliferative disorders?
- PV
- Essential Thrombocytosis
- Primary Myelofibrosis
What is Essential Thrombocytosis?
Neoplastic proliferation of mature myeloid cells in BM, especially platelets. (megakaryocytes are INC in #/size). +
- Leukocytosis/granulocytes
- Erythrocytosis
Mutations that cause Essential Thrombocytosis
- 50-60% = JAK2 point mutation: constitutive activation of JAK2 kinase (Valine = Phenylalanine at residue 617)
- 5-10% = MPL point mutation = constitutive activates MPL kinase
What will TPO levels be in Essential Thrombocytosis?
↓ TPO.
Clinical presentation of Essential Thrombocytosis
Symptoms due to ABNL platelets: ↑ risk of bleeding OR thrombosis
- Thrombosis (DVT, MI, stroke and portal/hepatic V. thrombosis)
- Hemorrhage
- Mild organomegaly
- Erythromelagia, throbbing and burning of hands and feet
How are Essential Thrombocytosis different from other Myeloproliferative Disorders?
- *RARELY progresses to marrow fibrosis/acute leukemia/
- *NO significant risk for hyperuricemia or gout
BM in Essential Thrombocytosis
- Mild Hypercellular
- ↑ megakaryocytes
- ABNL, many large platelets, with counts >1,000,000/mL
- Mild leukocytosis
What is Primary Myelofibrosis?
Neoplastic proliferation of mature myeloid cells in BM, especially megakaryocytes.
In Primary Myelofibrosis, how do INC in megakaryocytes cause problems?
- Releases PDGF & TGF-B
- => causes excess collagen production from NON-neoplastic fibroblasts
- => obliterative marrow fibrosis and scarring
Clinical Presentation of Primary Myelofibrosis
Medullary fibrosis causes
- Progressive anemia (normochromic, normocytic) => fatigue
- LUQ fullness due to marked splenomegaly due to extramedullary hemotopoeisis -sometimes only finding (like CML)
- Cytopenias
- Leukoerythroblastosis: Fibrosed marrow causes premature release of NUCLEATED erythroid and early granulocyte progenitors
- Increased risk of infection, thrombosis and bleeding => death
What histology finding do you see in Primary Myelofibrosis?
Teardrop-shaped red cells: tear-drop shaped RBC damaged by during release from fibrotic marrow
